Secondary lung infections remain a frequent and potentially life-threatening complication in individuals with chronic Human Immunodeficiency Virus (HIV). Unfortunately, the contributing factors to the >25-fold increased rate of pneumonia in HIV+ persons are not well defined. The fact that HIV+ persons with relatively preserved CD4-T-cell counts remain at high risk for bacterial pneumonia suggest the possibility that impaired function of other lung immune cells such as alveolar macrophages (AM) may contribute to pneumonia pathogenesis. AM express Toll-like receptors (TLR) that recognize conserved and essential molecular components of bacterial pathogens and activation of TLR initiates a crucial sequence of intracellular signaling cascades that result in effective clearance of invading bacteria. Recognizing the importance of TLR4 in recognition and biological response to bacterial LPS, preliminary data in this application demonstrate significant derangement of TLR4- mediated activation of AM from asymptomatic HIV+ subjects. Importantly, the derangement : a) is specific; b) may represent AM reprogramming to an LPS-tolerant phenotype; c) is in part attributed to HIV-targeting of specific AM regulatory molecules that influence host defense function; and d) is independent of HAART. Taken together, these provocative preliminary data support the central hypothesis that HIV infection of AM results in targeted and specific impairment of macrophage TLR mediated signaling pathways, impairing critical components of first line host defenses in the lungs. Testing the hypothesis will be accomplished through 3 specific aims: 1) To determine the anti-inflammatory signaling pathways selectively activated by HIV that modulate TLR-mediated host defense responses. 2) To determine the relative balance between MyD88-dependent and MyD88-independent signal transduction pathways in host defense function of AM from HIV+ persons in response to TLR4 activation. 3) To identify HIV-derived (Nef, gp120, ssRNA) and host-derived (IL-10) factors that contribute to HIV-mediated immune dysregulation in response to TLR4 activation in AM from HIV+ persons. Our goals are to define the molecular mechanism for HIV-induced impairment of AM TLR-mediated effector cell response, and to identify molecular targets that can enhance or rescue effector cell function (without triggering HIV replication) in AM from HIV+ persons at risk for bacterial pneumonia. These results will be used to develop new preventive and novel adjunctive strategies to treat AIDS-related pneumonia.